Triphenylpropyl amines



United States Patent 3,507,919 TRIPHENYLPROPYL AMINES Benjamin Blank, Trevose, and William A. Zuccarello, Philadelphia, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Apr. 27, 1967, Ser. No. 634,122 Int. Cl. C07c 87/28, 149/42, 145/00 U.S. Cl. 260-570 5 Claims ABSTRACT OF THE DISCLOSURE Novel substituted triphenylpropylamines having antiadrenal activity are disclosed, within which genus certain ring substituted 2,3,3 triphenylpropylamines showing selective anti-aldosterone activity. A process for their preparation starts with a benzophenone being converted to the corresponding benzhydryl halide. The halide is condensed with a phenyl acetonitrile to form a triphenylacetonitrile, which is reduced to the desired triphenylpropylamine.

Formula I CH2 my in which R and R are hydrogen or alkyl to 7 carbon atoms, preferably hydrogen;

R" is hydrogen, alkyl t0 7 carbon atoms, or phenyl, but

preferably hydrogen; and

Z and Z represent amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, acylamino having up to 3 carbon atoms, lower alkyl having up to 3 carbon atoms, lower alkoxy having up to 3 carbon atoms, lower alkylthio having up to 3 carbon atoms, lower alkylsulfinyl having up to 3 carbon atoms, lower alkylsnlfonyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, halo preferably chlorine, trifiuorornethyl, trifiuoromethylthio, trifluoromethylsulfonyl, trifiuoromethoxy, or hydrogen, with at least one of the Zs being other than hydrogen.

Advantageously, the substituted aliphatic amines, particularly those characterized by anti-aldosterone activity, are those represented by the above structure in which R, R and R" are all hydrogen, and one of Z or Z is amino, methyl, or methoxy.

Examples of specific compounds falling within Formula I are:

2- p-acetylphenyl -3 ,3 -diphenylpropylamine 2- (p-aminophenyl) -,3,3-diphenylpropylamine 3,507,919 Patented Apr. 21, 1970 3- (p-aminophenyl -2,3-diphenylpropylamine 2- p-tolyl -3 ,3-diphenylpropylamine 3 (ptolyl -2,3-diphenylpropylamine 2- (p-methylaminophenyl) -3 ,3 -diphenylpropylamine 3- (m-dimethylaminophenyl -2,3-diphenylpropylamine 2- (p-methoxyphenyl) -3 ,3 -dipheny1propylamine 3- m-ethylthiophenyl -2,3-diphenylpropylamine 2- (p-methylsulfinylphenyl -3 ,3-diphenylpropylamine 3- p-methylsulfonylphenyl) -2,3 -diphenylpropylamine 2- (p-acetamidophenyl -3 ,3-diphenylpropylamine 2- (p-phenyl -3 ,3-diphenylpropylamine 3- (m-chlorophenyl -2,3-diphenylpropylamine 3- (p-trifluoromethylphenyl -2,3-diphenylpropylamine 2- (p-chlorophenyl) -3 ,3-diphenylpropylamine 2- (p-rnethylthiophenyl -3,3-diphenylpropylamine 3- (p-methylthiophenyl) -2,3 -diphenylpropylamine 2- (p-trifluoromethylphenyl) -3 ,3-diphenylpropylamine 3- (m-trifluoromethylthiophenyl) -2,3-diphenylpropylamine 2- p-trifluor omethylsulfonylphenyl -3 ,3-diphenylp ropylamine 3- (m-trifiuoromethoxyphenyl -2,3-diphenylpropylamine Most advantageously, the compositions of this invention in dosage unit form comprise a nontoxic pharmaceutical carrier and one of the above-described antiadrenal compounds, or one of its acceptable acid addition salts.

It will be readily apparent to one skilled in this art that the substituted aliphatic amine compounds of this invention have one or two asymmetric carbon atoms, forming optically active dand l-compounds. The connotation of the general formulas presented herein is intended to include the separated d or l-optical isomers, as well as racemic mixtures of these isomers.

If desired, the isomers may be separated for individual use by resolution methods known to the art, such as fractional crystallization of the dibenzoyl-l-tartrate salts of the diamines. Alternatively, a synthesis starting with an optically active component may lead to the desired optical isomer.

The substituted aliphatic amine compounds of the instant invention are prepared as shown by the following synthetic scheme:

Z :i Reduction I V II HCOzH A In 0 a on HCOH I! y l 0 Z l I I l R([1-CH-OHz-NRR R"-(|)I?ICH2NHCOR I lII l Reduction I Z (XZ Y H -CH2NCH2R Generally, benzophenone or substituted benzophenones are treated with Grignard reagents to produce 1,1-diphenyl alkan-l-ols. These are fused with phenylacetonitrile or a substituted phenylacetonitrile, to give 3-alkyl- 2,3,3-triphenylpropionitrile. The substituted triphenylpropionitriles are novel intermediates. Catalytic hydrogenation or reduction with a metal hydride provides the desired amines.

Substituted triphenylpropylamines, as illustrated by Formula I (R, R and R"=hydrogen), and present in these novel compositions, are prepared by reduction with LiAlH or Al(i-OC H of an optionally substituted benzophenone, followed by halogenation of the resulting benzhydrol to give the corresponding benzhydryl halide. This halide is added to an optically substituted phenylacetonitrile to form the corresponding triphenylacetonitrile.

The nitrile intermediate is vigorously reduced using hydrogen and Raney nickel in methanol, or lithium aluminum hydride, to yield the desired optionally substituted triphenyl propylamine (Formula II).

The optionally substituted triphenyl propylamine may then be acylated with an appropriate acyl halide or anhydride to give the corresponding amide (Formula III) which is reduced with lithium aluminum hydride to the secondary amine (Formula IV).

A tertiary amine is prepared by treating the triphenyl propylamine with aqueous formaldehyde and formic acid to give the corresponding N,N-dimethyl-2,3,3-triphenylpropylamine (Formula I).

The preferred 2-aminophenyl substituted derivatives of this invention are prepared by protecting the amino group of the phenylacetonitrile with an acyl moiety, e.g., starting with an acetoamidophenylacetonitrile. Then by following the condensation procedure just outlined, one obtains a 2-acetoamidophenyl-3,3-diphenylproprionitrile. After hydrogenation, hydrolysis of the acetyl group may be accomplished by treatment with a strong mineral acid to give the corresponding 2-aminophenyl-3,3-diphenylpropylamine.

To obtain the 3-aminophenyl isomer, one starts with an acyl amino or nitro substituted benzhydryl halide and unsubstituted phenylacetonitrile. To obtain the bis aminophenyl congener, an acyl amino or nitro substituted benzhydryl halide and an acyl amino substituted phenylactonitrile are condensed as taught above.

Generally, triphenylalkylamines of Formula I may be obtained from the corresponding triarylalkanoic acid amides by reduction with lithium aluminum hydride. Exemplary syntheses are set forth in the examples.

To the best of our knowledge, only the unsubstituted analog of the claimed compounds has been mentioned in the literature, namely 2,3,3-triphenylpropylamine, but no antiadrenal activity of any type was attributed to it. It is reported by S. Wawzorek et al., J. Org. Chem. 16, 746-8 (1951).

More specifically, the pharmaceutical preparations and method of this. invention can be used whenever it is desired to suppress adrenal glandular function, thereby inhibiting the synthesis of certain adrenal steroids in order to control clinical conditions associated with adrenal hyperactivity, for example, edema. Also, they may be useful in the control of essential hypertension.

The pharmaceutical compositions of this invention are unique in that they also selectively lower the plasma level of the important adrenal steroid, aldosterone, at relatively low dosages, thereby promoting natruresis. Anti-adrenal activity has not been disclosed for compounds of the chemical class described hereinafter.

Further, the active ingredient of these compositions is rapidly absorbed, particularly from the gastrointestinal tract after oral administration, with remarkably low toX- icity within the dose ranges set forth hereinafter.

Exemplary of the utility of the here disclosed compounds in the treatment of edema, are in vivo studies carried out in sodium-depleted rats. It was found that 2-(paminophenyl)-3,3-diphenylpropylamine [SK & F 31,349] induced significant dose-related natruresis from 20 to 80 mg./kg., administered orally.

Exemplary of the direct and selective inhibition of aldosterone biosynthesis are in vitro studies carried out on the isolated halved adrenal glands of sodium-depleted rats. SK & F 31,349 significantly reduced aldosterone levels, at a molar concentration as low as 5 10- without a concomitant decrease in corticosterone or 18-hydroxy deoxycorticosterone levels, which eifect was also concentration related.

The acute oral LD of this compound (free base) in rats is about 1 g./kg. of body weight.

A nontoxic pharmaceutically acceptable organic or inorganic acid addition salt of the base defined in Formula I may be used instead of the base. Preferably, the hydrochloride salt is used. However, other salts such as those derived from sulfuric, nitric, phosphoric, citric, acetic, lactic, mandelic, salicylic, phthalic, fumaric, maleic, tartaric, hydrobromic, benzoic and like nontoxic acids may be used. The salts are :best prepared by reacting the free base with a stoichiometric amount of the desired organic or inorganic acid in a suitable solvent, such as ethyl acetate-ether solution, ethanol, acetone, water or various combinations of solvents. In addition to the acid addition salts, the quaternary amonium salts may be employed.

The pharmaceutical carrier employed may be, for example, either a' solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar,

. pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, ampul or liquid suspension.

The method in accordance with this invention comprises administering internally to an animal organism a compound as represented by the above formula, or a nontoxic addition salt thereof, usually combined with a pharmaceutical carrier, for example, any of the above compositions in an amount suflicient to produce antiadrenal activity. The active medicament preferably will be, typically per unit of hydrochloride salt, in an amount of from about 0.05 g. to about 1.5 g., and advantageously from about 0.1 g. to about 1.2 g. As a free base, the unit dosage will contain from about 0.05 g. to about 1 g. The administration may be parenterally or orally, the latter being the preferable route of administration. Advantageous ly equal doses will be administered two to twelve times daily. Preferably the daily dosage regimen will be from 0.05 g. to about 24 g., and most advantageously from about 0.5 g. to about 10.0 g. of active medicament in pharmaceutical forms. At the higher daily dosage, two or more capsules or tablets may be taken at each administration to attain the intended dosage level. When the administration described above is carried out, antiadrenal activity is effectively achieved.

In certain veterinary practices, the preparations can also be given per se, or as an additive to the feed or drinking matter of animals.

These preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary or variously mixing and dissolving the ingredients as appropriate to the desired end product.

The following examples are not limiting but are illustrative of pharmaceutical preparations of this invention.

Example l.Preparation of 2-(p-aminophenyl)-3,3-

diphenylpropylamine To a suitable reaction vessel charged with 112.45 g. (0.646 m.) of p-acetamidophenylacetonitrile in 200 ml. of dimethylformamide, is added 28.2 g. of sodium hydride with the temperature rising to about 45 C.

After the reaction mixture returns to room temperature, 74.9 ml. (0.646 m.) of benzhydrylchloride in 50 ml. of DMF is added, with the temperature again rising. The mixture is stirred for 15 minutes, and another 15 ml. of benzhydrylchloride in ml. of DMF is added, followed by further stirring for minutes.

The total reaction mixture is heated for one hour on a steam bath, then cooled, diluted with ice water, acidified with acetic acid, if necessary, and the solution is decanted from a gum which crystallizes from ethanol, to give a yellow solid which melts at 225 to 227 C.

A bomb is charged with the above nitrile and two teaspoons of Raney nickel catalyst No. 28 in methanol saturated with NH and hydrogen under an initial pressure of about 1180 lbs. per square inch are introduced. The vessel is rocked and slowly heated to about 80 C., maintaining that temperature for about three hours. During the heating process, additional hydrogen is charged to the vessel so as to maintain a hydrogen pressure of about 800 lbs. per square inch as a minimum. There is then isolated 137 g. of an off-white solid, Z-(p-acetamidophenyl)-3,3-diphenylpropylamine, M.P. 215-216 C.

The 2-(acetamidophenyl) 3,3 diphenylpropylamine (137 g.) is refluxed and stirred overnight with 210 ml. of concentrated hydrochloric acid, 421 ml. of acetic acid and 421 ml. of water. An additional 50 ml. of acetic acid is added. The mixture is refluxed and stirred for another 5 hours, then cooled, and concentrated to give 2- (p-aminophen'yl)-3,3-diphenylpropylamine as the dihydrochloride.

The propylamine is recrystallized twice from a methanol-ethyl acetate mixture, then is dried in vacuo. The melting point of the product is 320 C.

Example 2.-Preparation of 2,3-diphenyl-3-(substituted phenyl)propionitriles Phenylacetonitrile (0.0167 mole) in 10 ml. of dimethylformamide is added to a stirred suspension of 0.0167

mole of sodium hydride in 30 ml. of dimethylformamide. After return to room temperature, 0.0184 mole of the appropriately substituted (Z other than H) benzhydryl halide in 10 ml. of dimethylformamide is added to the stirred mixture. The mixture is stirred 30 minutes at room temperature, then heated on a steam bath for 1 hour. The mixture is cooled, water is added carefully and the mixture is then diluted with several volumes of ice-water, acidified with acetic acid if still basic, and extracted with ethyl acetate.

The ethyl acetate is washed with water and dried over sodium sulfate. The ethyl acetate is concentrated to give an oil.

Similarly, the following specific compounds are prepared:

2,3-diphenyl-3-(p trifluoromethylphenyl)propionitrile is crystallized from methanol and recrystallized from ethanol, to give crystals melting at 180182 C.

2,3-diphenyl-3 (p methylthiophenyl)propionitrile is put on a silica gel (-200 mesh) column, and eluted with 2:1 benzenepetroleum ether. The silicates are concentrated to a gum. The gums solidify when triturated with methanol, and the solid is recrystallized from benzenepetroleum ether to give crystals melting at 128- 130 C.

Example 3.Preparation of 2,3-diphenyl-3-(p-methylsulfonylphenyl)propionitrile 2,3-diphenyl-3-(p methylthiophenyl)propionitrile (18 grams, 0.055 mole) is stirred in 170 ml. of glacial acetic acid, and 100 ml. of 30% hydrogen peroxide is added dropwise. The solution is stirred 15 minutes at room temperature, heated two hours on a steam bath, then cooled and diluted with several volumes of ice-water. The mixture is extracted with chloroform, the chloroform was washed with water, 5% sodium bicarbonate solution, and water dried over sodium sulfate. The chloroform is concentrated to give a brown gum which was dissolved in EtoAc-cyclohexane (1:1), placed on a silica gel column, and eluted with EtoAc-cyclohexane (1:1). The fractions are evaporated and crystallized when triturated with chloroform. The material is recrystallized from chloroform-petroleum ether to give a solid melting at -142" C., with bubbling.

Example 4.Preparation of 3,3-diphenyl-2-(substituted phenyl)propionitriles The appropriately substituted (Z other than H) phenylacetonitrile (0.19 mole) in 30 ml. of dimethylformamide is added dropwise to a stirred suspension of 0.19 mole of sodium hydride in 40 ml. of dimethylformamide. When the temperature of the reaction returns to room temperature, 0.19 mole of chlorodiphenylmethane in 20 ml. of dimethylformamide is added dropwise below 50 C. The mixture is stirred 30 minutes at room temperature, then heated 1 hour on a steam bath. The mixture is cooled, water is added carefully and the mixture was diluted with several volumes of ice-water, and acidified with acetic acid, if still basic. The mixture is extracted with ethyl acetate. The ethyl acetate is washed with water, dried over sodium sulfate, and concentrated to give an oil.

Similarly, the following specific compounds are prepared:

3,3 dipheny1-2-(p-tolyl)propionitrile is crystallized from methanol, and recrystallized from hexane to give crystals melting at 88-89 C.

3,3 diphenyl-Z-(p-methylthiophenyl)propionitrile is dissolved in benzene-petroleum ether (1:1), placed on a silica gel column, and eluted with benzene. The eluants are concentrated to give gums, which were crystallized and recrystallized from methanol, to give crystals melting at 104-105 C.

3,3 diphenyl 2 (p-methoxyphenyl)propionitrile is crystallized and recrystallized from methanol to give crystals melting at 133134 C.

2 (p-chlorophenyl)-3,3-diphenylpropionitrile is crystallized and recrystallized from methanol to give crystals melting at 123-125 C.

3,3 diphenyl-2-(p-methylsulfonylphenyl)propionitrile is recrystallized from methanol-Water to give crystals melting at 160-162 C.

Example 5.Preparation of 3,3-diphenyl-2-(p-tolyl) propylamine hydrochloride 3,3 diphenyl-2-(p-tolyl)propionitrile (0.0664 mole) is reduced with Raney nickel in methanol saturated with ammonia at 80 C. under 1000 p.s.i. of hydrogen. The catalyst is filtered oif, the filtrate was concentrated to give a semi-solid mass which is treated with 10% sodium hydroxide, extracted into ethyl acetate, dried, and added to a stirred solution of ethereal hydrogen chloride to precipitate a white solid.

The solid is recrystallized from alcohol-ether to give material melting at 254-257 C.

Example 6.-Preparation of 3,3-diphenyl-2-(substituted phenyl)propylamines and 2,3 diphenyl-3-(substituted phenyl)propylamines The appropriately substituted 2,3,3-triphenyl propionitrile (0.009 mole) is dissolved in tetrahydrofuran, and added dropwise to a suspension of 0.027 mole of lithium aluminum hydride in 120 ml. of ether. The mixture is refluxed for 3 hours, cooled, the complex is decomposed by 1 ml. of water for each gram of lithium aluminum hydride, followed by 1 ml. of 10% sodium hydroxide for each gram of lithium aluminum hydride, and 3 ml. of water per gram of lithium aluminum hydride.

The mixture is stirred for 45 minutes, filtered, the filter cake is washed with ether and the filtrate is concentrated to dryness. The residue is evaporated several times with alcohol, and converted to the desired salt.

Similarly, the following specific compounds are prepared:

3,3 diphenyl-Z-(p-methoxyphenyl)propylamine hydrochloride is recrystallized from ethanol ether to give a solid melting at 230-232 C.

3,3 diphenyl-2-(p-methylthiophenyl)propylamine hydrochloride monohydrate is recrystallized from ethanolether to give crystals melting at 140 C.

2 (p-chlorophenyl)-3,3-diphenylpropylamine hydrochloride is recrystallized from n-butanol-ether to give a solid melting at 274276 C.

2,3 diphenyl-3-(p-trifiuoromethylphenyl)propylamine hydrochloride is recrystallized from ethylacetate-petroleum ether to give crystals melting at 223224 C.

2,3 diphenyl-3-(p-methylthiophenyl)propylamine hydrochloride is recrystallized from ethanol-ether petroleum ether to give a solid melting at 236-238" C.

Example 7.Preparation of N-ethyl-2,3-diphenyl-3-(ptrifluoromethylphenyl) propylamine hydrochloride (Formula IV) To a stirred solution of 2,3-diphenyl-3-(p-trifluoromethylphenyl)propylamine hydrochloride (Example 6) and sodium acetate in water is added acetic anhydride. The mixture is stirred for several hours. During this time additional sodium acetate was added to keep the pH of the mixture at 5-6. The mixture is cooled, the pre cipitated amide is filtered, washed with water, recrystallized, and dried.

The dried amide, dissolved in dry tetrahydrofuram'is added dropwise to a stirred suspension of lithium aluminum hydride in tetrahydrofuran. The mixture is stirred under reflux for 6 hours, and cooled. The complex is decomposed by the careful addition of dilute base.

The granular precipitate is filtered and washed with tetrahydrofuran. The filtrate is concentrated, the residue is dried by azeotropic distillation of benzene, and the dried residue is dissolved in ethyl acetate and added to ethereal hydrogen chloride. The hydrochloride is filtered and recrystallized.

8 Example 8.N,N-dimethyl-2,3-diphenyl-2-(p-tolyl) propylamine hydrochloride (Formula I) The above ingredients are screened through a #40 mesh screen, mixed well and filled into a #1 hard gelatin capsule. One capsule is administered two to twelve times daily.

Example 10 Ingredients: Amounts, mg.

2 (p aminophenyl)-3,3-diphenylpropylamine hydrochloride 100.00 Magnesium stearate 5.00 Lactose 400.00

The above ingredients are screened through a #40 mesh screen, mixed well and filled into a #0 hard gelatin capsule. One capsule is administered two to twelve times a day.

Example 11 Ingredients Amounts, mg.

2- (p-methylphenyl) -3 3-diphenylpropylamine 25.00 Calcium sulfate, dihydrate 125.00 Sucrose 25 .00

Starch 15.00

Talc 5.00 Stearic acid 3.00

The sucrose, calcium sulfate and 2 -(p-methylphenyl)- 3,3-diphenylpropylamine are thoroughly mixed and granulated with 10% hot gelatin solution. The wetted mass is passed through a#6 mesh screen directly onto drying trays. The granules are dried at F. and passed through a #20 mesh screen. These granules are then mixed with the starch, talc and stearic acid, passed through a #60 mesh screen and compressed into tablets.

Example 12 Ingredients: Amounts, mg.

-2- p-methoxyphenyl) -3 ,3 -diphenylpropylamine 150.00 Peanut oil 200.00

The ingredients are mixed to a thick slurry and filled into a soft gelatin capsule. One capsule is administered two to twelve times a day.

Also highly useful forms are sustained time release compositions which provide a substantially uniform dosage over an extended period of time, thus permitting reduction of the number of unit doses to be taken daily.

We claim:

1. A chemical compound, or acid addition salt thereof, having the structural formula:

HZQQ.

in which 5. A compound according to claim 2 wherein Z is R and R are hydrogen or lower alkyl having up to 2 p-methoxy.

carbon atoms;

R" is hydrogen; References Cited Z and) Z' ripreselilh aillriliilo, alkyllamino llliavtingsup E80: 5 UNITED STATES A TS car on a oms, 1a y ammo avlng p 0 car atoms, alkyl having up to 3 carbon atoms, lower ggigga ISDheItOH et i g alkoxy having up to 3 carbon atoms, lower alkylthio 0 0 auto et a 7 having up to 3 carbon atoms, lower alkylsulfinyl OTHER REFERENCES having up to 3 carbon atoms lower alkylsqlfonyl 1O Wawzonek et al.: Journal Organic Chemistry, vol. having up to 3 carbon atoms, lower acyl havmg up 16 Pages 74648 (1951).

to 3 carbon atoms, halo, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyl, trifluoromethoxy ROBERT HINES P Exam' or hydrogen, with at least one of the Zs being other nmary met 2 than hydrogen d, 1 h R R, 15 US. Cl. X.R.

A 9 mg mm W 260-465, 607, 609, 562, 649, 390, 591, 592, 612, 501.1, R andZ are all hydrogen. 5 6 8. 4

3. A compound according to claim 2 wherein Z is 55 42 330 p-amino.

4. A compound according to claim 2 wherein Z is 20 p-methyl. 

